Coverage Policy Manual
Policy #: 2018000
Category: Medicine
Initiated: September 2018
Last Review: July 2022
  Leadless Cardiac Pacemakers

Description:
Pacemakers are intended to be used as a substitute for the heart’s intrinsic pacing system to correct cardiac rhythm disorders. By providing an appropriate heart rate and heart rate response, cardiac pacemakers can reestablish effective circulation and more normal hemodynamics that are compromised by a slow heart rate. Pacemakers vary in system complexity and can have multiple functions as a result of the ability to sense and/or stimulate both the atria and the ventricles.
 
Transvenous pacemakers or pacemakers with leads (here after referred as conventional pacemakers) consist of 2 components: a pulse generator (also referred to as battery component) and electrodes (also referred to as leads). The pulse generator consists of a power supply and electronics that can provide periodic electrical pulses to stimulate the heart. It is commonly implanted in the infraclavicular region of the anterior chest wall and generally placed in a pre-pectoral position, but in some cases a sub-pectoral position is advantageous. It generates the electrical impulse which is transmitted to the myocardium via the electrodes affixed to the myocardium to sense and pace the heart as needed.
 
Epicardial leads or leads put on the surface of the heart have been used for years.  Temporary epicardial leads are used on most patients post cardiac surgery and are placed at the time of surgery.  Permanent atrial and ventricular epicardial leads are still used commonly in pediatric heart surgery in patients too small for endocardial leads.  The wires from the epicardial electrode are brought out to a subcutaneous pocket often in the upper abdomen where a conventional pacemaker generator can be connected and implanted.  Epicardial pacemaker leads often require higher thresholds than endocardial lead. This may worsen over time and cause more rapid drain of the pacemaker generator battery. In the modern era of minimally invasive surgery the leads can be placed through small incisions or thoracoscopically.
 
Conventional pacemakers are also referred to as single-chamber or dual-chamber systems. In single-chamber systems, only 1 lead is placed, typically in the right ventricle. In dual-chamber pacemakers, 2 leads are placed-one in the right atrium and the other in right ventricle. Single-chamber ventricular pacemakers are much more commonly used in practice.
 
Annually, approximately 200,000 pacemakers are implanted in the United States and 1 million worldwide (Reddy, 2015). Implantable pacemakers are considered life-sustaining, life-supporting class III devices for patients with variety of bradyarrhythmias. Pacemaker systems have matured over the years with well-established, acceptable performance. As per the Food and Drug Administration (FDA), the early performance of conventional pacemaker systems from implant through 60 to 90 days has usually demonstrated acceptable pacing capture thresholds and sensing. Intermediate performance from 90 days through more than 5 years has usually demonstrated reliability of the pulse generator and lead technology. Chronic performance from 5 to 10 years includes a predictable decline in battery life and mechanical reliability but a vast majority of patients receive excellent pacing and sensing free of operative or mechanical reliability failures.
 
The potential advantages of leadless pacemakers fall into 3 categories: avoidance of risks associated with intravascular leads in conventional pacemakers, avoidance of risks associated with pocket creation for placement of conventional pacemakers, and an additional option for patients who require a single chamber pacer (AHA, 2016).
 
• Lead complications include lead failure, lead fracture, insulation defect, pneumothorax, infections requiring lead extractions/replacements that can results in a torn subclavian vein or tricuspid valve. In addition, there are potential risk of venous thrombosis and occlusion of the subclavian system from the leads. Use of a leadless system eliminates such potential risks with the added advantage that patient has vascular access preserved for other medical conditions (eg, dialysis or chemotherapy).
• Pocket complications include infections, erosions and pain that can be eliminated with leadless pacemakers. Further, a leadless cardiac pacemaker may be more comfortable and appealing as unlike conventional pacemakers, patients are unable to see or feel or have implant scar on the chest wall with leadless pacemakers.
• Lastly, leadless pacemakers may also be a better option than a surgical endocardial pacemaker for patients with no vascular access due to renal failure or congenital heart disease.
 
Leadless pacemakers are self-contained in a hermetically sealed capsule. The capsule houses a battery and electronics to operate the system. Similar to most pacing leads, the tip of the capsule includes a fixation mechanism and a monolithic controlled release device. The controlled release device elutes glucocorticosteroid to reduce acute inflammation at the implantation site. Leadless pacemakers have rate responsive functionality, and current device longevity estimates are based on bench data. Estimates have shown that these devices may last over 10 years depending on the programmed parameters (FDA, 2016).
 
Three systems are currently being evaluated in clinical trials: (1) the Micra Transcatheter Pacing System (Medtronic), (2) the Aveir VR Leadless Pacemaker (Abbott; formerly Nanostim, St. Jude Medical); and (3) the WiCS Wireless Cardiac Stimulation System (EBR Systems). The first 2 devices are free-standing capsule-sized devices that are delivered via femoral venous access using a steerable delivery sheath. However, the fixing mechanism differs between the 2 devices. In the Micra Transcatheter Pacing System, the fixation system consists of 4 self-expanding nitinol tines, which anchor into the myocardium; for the Aveir device, there is a screw-in helix that penetrates into the myocardium. In both devices, the cathode is steroid eluting and delivers pacing current; the anode is located in a titanium case. The third device, WiCS system differs from the other devices; this system requires implanting a pulse generator subcutaneously near the heart, which then wirelessly transmits ultrasound energy to a receiver electrode implanted in the left ventricle. The receiver electrode converts the ultrasound energy and delivers electrical stimulation to the heart sufficient to pace the left ventricle synchronously with the right (FDA, 2016).
 
Of these 3, only the Micra and Aveir single-chamber transcatheter pacing systems are approved by the FDA and commercially available in the U.S. Multiple clinical studies of the Aveir predecessor device, Nanostim, have been published but trials have been halted due to the migration of the docking button in the device and premature battery depletion (Reddy, 2015; Reddy, 2016; Reddy, 2014; Knopps, 2015; Lakkireddy, 2017; Sperzel, 2018). These issues have since been addressed with the Aveir device (Reddy, 2022).
 
The Micra is about 26 mm in length and introduced using a 23 French catheter via the femoral vein to the right ventricle. It weighs about 2 grams and has an accelerometer-based rate response (Zuckerman, 2016).
 
The Aveir is about 42 mm in length and introduced using a 25 French catheter to the right ventricle. It also weighs about 3 grams and uses a temperature-based rate response sensor (FDA, 2022).
 
Regulatory Status
In April 2016, Micra® Transcatheter Pacing System (Medtronic) was approved by FDA through the premarket approval process for use in patients who have experienced 1 or more of the following conditions:
 
• symptomatic paroxysmal or permanent high-grade AV block in the presence of atrial fibrillation (AF)
• paroxysmal or permanent high-grade AV block in the absence of AF, as an alternative to dual chamber pacing, when atrial lead placement is considered difficult, high risk, or not deemed necessary for effective therapy
• symptomatic bradycardia-tachycardia syndrome or sinus node dysfunction (sinus bradycardia or sinus pauses), as an alternative to atrial or dual chamber pacing, when atrial lead placement is considered difficult, high risk, or not deemed necessary for effective therapy.
 
In January 2020, the Micra AV Transcatheter Pacing System Model MC1AVR1 and Application Software Model SW044 were approved as a PMA supplement (S061) to the Micra system described above. The Micra AV includes an enhanced algorithm to provide AV synchronous pacing.
 
In November 2021, the U.S. FDA issued a letter to health care providers regarding the risk of major complications related to cardiac perforation during implantation of leadless pacing systems (FDA, 2022). Specifically, the FDA states that "real-world use suggests that cardiac perforations associated with Micra leadless pacemakers are more likely to be associated with serious complications, such as cardiac tamponade or death, than with traditional pacemakers."
 
In March 2022, the Aveir™ VR Leadless Pacemaker was approved by the U.S. FDA through the premarket approval process (PMA number: P150035) for use in patients with bradycardia and:
 
    • normal sinus rhythm with only rare episodes of A-V block or sinus arrest
    • chronic atrial fibrillation
    • severe physical disability.
 
Rate-Modulated Pacing is indicated for patients with chronotropic incompetence, and for those who would benefit from increased stimulation rates concurrent with physical activity.

Policy/
Coverage:
Effective October 15, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Micra single-chamber transcatheter pacing system meets primary coverage criteria when all of the following are met:
 
        1. Patient has indications for right ventricular single-chamber pacing.
        2. Patient has a significant contraindication to placement of traditional pacemaker leads, such as recurrent lead fracture, recent lead infection, tricuspid valve abnormality precluding placement of a lead, or congenital/acquired venous abnormalities that preclude access to the heart.  
        3. The patient is not a candidate for epicardial pacemaker leads.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Use of the Micra single-chamber transcatheter pacing system for any indication or condition not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of the Micra single-chamber transcatheter pacing system for any indication or condition not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Use of the Aveir single-chamber transcatheter pacing system for all indications does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of the Aveir single-chamber transcatheter pacing system for all indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless left ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless left ventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless bi-ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless bi-ventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 2019 through October 15, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Micra Transcatheter Pacing System meets primary coverage criteria when all of the following are met:
 
    1. Patient has indications for right ventricular single-chamber pacing.
    2. Patient has a significant contraindication to placement of traditional pacemaker leads, such as recurrent lead fracture, recent lead infection, tricuspid valve abnormality precluding placement of a lead, or congenital/acquired venous abnormalities that preclude access to the heart.  
    3. The patient is not a candidate for epicardial pacemaker leads.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Use of a leadless pacemaker for all other indications, does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of  a leadless pacemaker implant for all other indications is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless left ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless left ventricular pacing is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless bi-ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless bi-ventricular pacing is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to August 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Micra Transcatheter Pacing System meets primary coverage criteria when all of the following are met:
 
      1. Patient has indications for right ventricular single-chamber pacing.
      2. Patient has a significant contraindication to placement of traditional pacemaker leads, such as recurrent lead fracture, recent lead infection, tricuspid valve abnormality precluding placement of a lead, or congenital/acquired venous abnormalities that preclude access to the heart.  
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Use of a leadless pacemaker for all other indications, does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of  a leadless pacemaker implant for all other indications is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless left ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless left ventricular pacing is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Leadless bi-ventricular pacing does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of leadless bi-ventricular pacing is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Micra Transcatheter Pacing System meets primary coverage criteria when all of the following are met:
 
    1.  Patient has indications for right ventricular single-chamber pacing.
    2. Patient has a significant contraindication to placement of traditional pacemaker leads, such as recurrent lead fracture, recent lead infection, tricuspid valve abnormality precluding placement of a lead, or congenital/acquired venous abnormalities that preclude access to the heart.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Use of the Micra Transcatheter Pacing System for all other indications, does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, use of  a leadless pacemaker implant for all other indications is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
This evidence review was created in August 2018 with a search of the MEDLINE database through July 18, 2018.
 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
 
Conventional pace makers systems have been in use for over 50 years and the current available technology has matured with significant similarities of device design across models. Extensive bench testing experience with conventional pacemakers and a good understanding of operative and early postimplant safety and effectiveness is available which limits the need for collection of clinical data to understand their safety and effectiveness with regard to implant, tip fixation, electrical measures, and rate response. As such, a randomized trial comparing the leadless pacemakers with conventional pacemakers was not required by the Food and Drug Administration (FDA).
 
INDIVIDUALS WITH GUIDELINES-BASED INDICATION FOR A VENTRICULAR PACING SYSTEM WHO ARE MEDICALLY ELIGIBLE TO RECEIVE A CONVENTIONAL PACING SYSTEM
 
Clinical Context and Therapy Purpose
The purpose of Micra Transcatheter Pacing System in patients with a class I or II guidelines-based indication for implantation of a single chamber ventricular pacemaker is to provide a treatment option that is an alternative to or an improvement on conventional pacing systems.
 
The question addressed in this evidence review is: Does use of the Micra Transcatheter Pacing System improve the net health outcome in patients with patients with a class I or II guidelines-based indication for implantation of a single-chamber ventricular pacemaker who are medically eligible to receive a conventional pacing systems?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant population of interest is patients with a class I or II guidelines-based indication for implantation of a single chamber ventricular pacemaker who are medically eligible to receive conventional pacing system.
 
Interventions
The therapy being considered is the Micra Transcatheter Pacing System.
 
Comparators
The following therapy is currently being used to make decisions about managing patients requiring a pacemaker: a conventional pacemaker.
 
Outcomes
The general outcomes of interest are treatment-related mortality and morbidity. Specifically, the short-term outcomes include acute complication-free survival rate, electrical performance of the device including pacing capture threshold and adverse events including procedural and postprocedural complications. Long-term outcomes include chronic complication-free survival rate, electrical performance of the device including pacing impedance and pacing thresholds and chronic complications including any system explant, replacement (with and without system explant) and repositions. Further, analysis summary statistics regarding battery length are deemed crucial as well.
 
Timing
To assess short-term safety, the first 30 days postimplant is generally considered appropriate as majority of device and procedural complications occur within this time frame. To assess long-term efficacy and safety as well issues related to end of life of the device, follow up to 9 to 12 years postimplant with
adequate sample size are required to characterize device durability and characterize infrequent complications with sufficient certainty.
 
Setting
Cardiac pacemaker implant is performed by interventional cardiologists in the electrophysiology laboratory.
 
Nonrandomized Controlled Trials
 
Pivotal Trial
The pivotal investigational device exemption (IDE) trial was a prospective single cohort study in which 744 patients with class I or II indication for implantation of a single chamber ventricular pacemaker according to ACC/AHA/HRS 2008 guidelines and any national guidelines were enrolled. The details on the design (Ritter, 2015) and results of the IDE trial have been published (Ritter, 2015; Reynolds, 2016).. System performance from the pivotal trial has been published (Lloyd, 2017) but results are not discussed further.
 
Of the 744 patients, the implantation of the Micra Transcatheter Pacing System was attempted in 725 patients of whom 719 (99.2%) were successfully implanted. The demographics of the trial population were typical for a single chamber pacemaker study performed in the United States with 42% being female and average age was 76 years. Sixty-four percent had a pacing indication associated with persistent or permanent atrial arrhythmias, 72.6% had any atrial fibrillation at baseline, and 27.4% did not have a history of atrial fibrillation. Among those 27.4% (n=199) without atrial fibrillation, 16.1% (n=32) had a primary indication of sinus bradycardia and 3.5% (n=7) had a primary indication of tachycardia-bradycardia (Reynolds, 2016).
 
The IDE trial had 2 primary end points related to safety and efficacy. The trial would have met the safety end point if the lower bound of the 95% confidence interval (CI) for the rate of freedom from major complications related to the Micra Transcatheter Pacing System or implantation procedure exceeded 83% at 6 months. Major complications were defined as those resulting in any of the following; death, permanent loss of device function due to mechanical or electrical dysfunction of the device (eg, pacing function disabled, leaving device abandoned electrically), hospitalization, prolonged Hospitalization by at least 48 hours or system revision (reposition, replacement, explant) (FDA, 2018). The trial would have met the efficacy end point if the lower bound of the 95% CI for the proportion of patients with adequate pacing capture thresholds (PCT) exceeded 80% at 6 months. PCT as an effectiveness objective is a common electrical measure of pacing efficacy and is consistent with recent studies. Pacing capture threshold measured in volts is defined as the minimum amount of energy needed to capture the myocardial tissue electrically. Unnecessary high pacing output adversely shortens the battery life of the pacemaker and is influenced by physiologic and pharmacologic factors (FDA, 2018). As per FDA, demonstrating that “PCT is less than 2 Volts for the vast majority of subjects will imply that the Micra Transcatheter Pacing System will have a longevity similar to current pacing systems since Micra’s capture management feature will nominally set the safety margin to 0.5 volts above the PCT with hourly confirmation of the PCT” (FDA, 2018).
 
At 6 months, the trial met both the efficacy and safety primary end points including freedom from major complications related to the system or procedure in 96.0% of the patients (95% CI, 93.9% to 97.3%), compared with a performance goal of 83%, and an adequate pacing capture threshold in 98.3% of the patients (95% CI, 96.1% to 99.5%), compared with a performance goal of 80% (Reynolds, 2016).
 
The results of the IDE trial were compared post hoc with a historical cohort of 2667 patients generated from the six previous pacemaker studies conducted between 2005 and 2012 by Medtronic that evaluated performance requirement at 6 months post implant of right ventricle pacing leads (single-chamber rates obtained by excluding any adverse events that were only related to the right atrial lead from the analysis). Micra Transcatheter Pacing System was associated with fewer complication than the historical control (4.0% vs 7.4%; hazard ratio [HR], 0.49; 95% CI, 0.33 to 0.75; p=0.001) (Reynolds, 2016). Because there were differences in the baseline patient characteristics between the 2 cohorts (patients in the historical cohort were younger and with lower prevalence of coexisting conditions vs the IDE trial), an additional propensity-matched analysis was also conducted that showed similar result (HR=0.46; 95% CI, 0.28 to 0.74). As per FDA, lower rate of major complication with Micra Transcatheter Pacing System were driven by reductions in access site events (primarily implant site hematoma and implant site infections), pacing issues (primarily device capture and device pacing issues), and fixation events (there were no device/lead dislodgements in the Micra IDE trial) (FDA, 2016).
 
While the overall rate of complication was low, the rate of major complications related to cardiac injury (ie., pericardial effusion or perforation) was higher in the Micra IDE trial than in the 6 reference Medtronic pacemaker studies (1.6% vs 1.1%, p=0.288). Thus, there appears to be a trade-off between types of adverse events with Micra Transcatheter Pacing System and conventional pacemakers. While adverse events related to leads and pocket are eliminated or minimized with Micra Transcatheter Pacing System, certain adverse events such as groin vascular complications and vascular/cardiac bleeding occur at a higher frequency or are additive (new events) than conventional pacemakers. Of these, procedural complications such as acute cardiac perforations that were severe enough to resulting result in tamponade and emergency surgery were most concerning (FDA, 2016).
 
In addition to lack of adequate data on long-term safety, effectiveness, reliability, and incidence of late device failures and battery longevity, there is also inadequate clinical experience with issues related to devices that have reached end of life including whether to extract or leave the device in situ and possibility of device-device interactions (FDA, 2016). There is no data on device-device interactions (both electrical and mechanical), which may occur when there is a deactivated Micra device alongside another leadless pacemaker or when a leadless pacemaker and transvenous device are both present. Even though, there have only been few device retrievals and very limited experience with time course of encapsulation of these devices in humans, it is highly likely that these devices will be fully encapsulated by the end of its typical battery life, and therefore device retrieval is unlikely.19 Current recommendations for end-of-device-life care for a Micra device may include the addition of a replacement device with or without explantation of the Micra device, which should be turned off (Medtronic, 2018).
 
Post Approval Study
The FDA approval of the Micra Transcatheter Pacing System is contingent on multiple postapproval studies to ensure reasonable assurance of continued safety and effectiveness of the device. Among these, the Micra Transcatheter Pacing System Post-Approval Study, a global, prospective, observational, multi-center study, enrolled 1830 patients to ensure that data is available for 1741 patients to estimate acute complication rate within 30 day of the implant, 500 patients to estimate 9-year complication free survival rate, and a minimum of 200 patients with a Micra Transcatheter Pacing System revision for characterizing end of device service.18 As per the protocol, if a subsequent device is placed and the Micra is deactivated or explanted, Medtronic would contact the implanting center and request the patient's clinical data surrounding the revision. All such data would be summarized including the type of system revision, how the extraction was attempted, success rate, and any associated complications (FDA, 2016).
 
The postapproval study completed enrollment in early March 2018. The definition of major complication in the postapproval study was same as the Micra IDE trial. It is unclear if any patients who participated in the IDE trial were also enrolled in the post approval study.
 
At 30 days, the major complication rate was 1.51% (95% CI, 0.78 to 2.62%). The major complication rate was lower in the postapproval study compared with IDE trial (odds ratio [OR], 0.58; 95% CI, 0.27 to 1.25) although this did not reach statistical difference. The lower major complications was associated with a
decrease in events that led to hospitalization, prolonged hospitalization, or loss of device function in the postapproval study compared to the IDE trial (Roberts, 2017).  
 
After a mean follow-up of 6.8 months, the major complication rate was 2.7% (95% CI, 2.0% to 3.6%). Authors compared these results with the same historical cohort of 2667 patients used in the IDE trial and reported a 63% reduction in the risk for major complications through 12 months with Micra Transcatheter Pacing System relative to conventional pacemakers (HR=0.37; 95% CI, 0.27 to 0.52). Additionally, the risk for major complication was lower in the Micra postapproval study than in the IDE trial but it was statistically significant different (HR= 0.71, 95% CI, 0.44 to 1.1) (Mikhael, 2018). However, details of events classified as major complications were not reported for the historical control or for the IDE trial cohort at 1 year and therefore it is unclear as to which events were decreased in the post approval study or if any events increased with Micra Transcatheter Pacing System.
 
Section Summary: Individuals With Guidelines-Based Indication for a Ventricular Pacing System who are Medically Eligible to Receive a Conventional Pacing System
The evidence for use of Micra Transcatheter Pacing System consists of a pivotal prospective cohort study and a postapproval prospective cohort study. Results at 6 months and 1 year for the pivotal study reported high procedural success (above 99%) and device effectiveness (pacing capture threshold met in 98% patients). Majority of the system or procedural-related complications occur within 30 days. At 1 year, the incidence of major complication did not increase substantially from 6 months (3.5% at 6 months versus 4% at 1 year). Results of the postapproval study were consistent with pivotal study and showed a lower incidence of major complications at -30 days as well as 1 year (1.5% and 2.7%, respectively). In both studies, the point estimates of major complication were lower than the pooled estimates from 6 studies of conventional pacemakers used as a historical comparator. While Micra Transcatheter Pacing System eliminates adverse events associated with lead and pocket issue, its use results in additional complication related to the femoral access site (groin hematomas and access site bleeding) and implantation/release of the device (traumatic cardiac injury). Considerable uncertainties and unknowns remain in terms of durability of device and end of life device issues. Early and limited experience suggests that retrieval of these devices is unlikely because in due course of time, the devices will be encapsulated. There is limited data on device-device interactions (both electrical and mechanical), which may occur when there is a deactivated Micra device alongside another leadless pacemaker or when a leadless pacemaker and transvenous device are both present.
 
INDIVIDUALS WITH GUIDELINES-BASED INDICATION FOR A VENTRICULAR PACING SYSTEM WHO ARE MEDICALLY INELIGIBLE FOR A CONVENTIONAL PACING SYSTEM
 
Clinical Context and Therapy Purpose
The purpose of Micra Transcatheter Pacing System in patients with a class I or II guidelines-based indication for implantation of a single chamber ventricular pacemaker is to provide a treatment option that is an alternative to or an improvement on conventional pacing systems.
 
The question addressed in this evidence review is: Does use of the Micra Transcatheter Pacing System improve the net health outcome in patients with patients with a class I or II guidelines-based indication for implantation of a single chamber ventricular pacemaker who are medically ineligible for a conventional pacing system?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant population of interest is patients with a class I or II guidelines-based indication for implantation of a single chamber ventricular pacemaker who are medically ineligible for a conventional pacing system.
 
Interventions
The therapy being considered is Micra Transcatheter Pacing System.
 
Comparators
The following therapy and practice are currently being used to make decisions about managing patients ineligible for a conventional pacemaker: medical management and/or conventional pacemakers.
 
Outcomes
The general outcomes of interest are treatment-related mortality and morbidity. Specifically, the short-term outcomes include acute complication-free survival rate, electrical performance of the device including pacing capture threshold and adverse events including procedural and postprocedural
complications. Long-term outcomes include chronic complication-free survival rate, electrical performance of the device including pacing impedance and pacing thresholds and chronic complications including any system explant, replacement (with and without system explant) and repositions. Further, analysis summary statistics regarding battery length are deemed crucial as well.
 
Timing
To assess short-term safety, the first 30 days postimplant is generally considered appropriate as majority of device and procedural complications occur within this time frame. To assess long-term efficacy and safety as well issues related to end of life of the device, follow up to 9 to 12 years postimplant with adequate sample size are required to characterize device durability and characterize infrequent complications with sufficient certainty.
 
Setting
Cardiac pacemaker implant is performed by interventional cardiologists in the electrophysiology laboratory.
 
Nonrandomized Controlled Trials
No studies that exclusively enrolled patients who were medically ineligible to receive a conventional pacing system were identified.
 
In the IDE trial, 6.2% or 45 patients received the Micra Transcatheter Pacing System because they were medically ineligible to receive a conventional pacing system such as compromised venous access, the need to preserve veins for hemodialysis, thrombosis, a history of infection, or the need for an indwelling venous catheter.
 
In the postapproval registry whose early results have been published only as an abstract, authors reported stratified results of 99 of 1744 patients who had previous cardiac implantable electronic device (CIED) infection (Mikhael, 2018). Of these 99, 78 (79%) were classified as medically ineligible to receive a conventional pacemaker in the opinion of physician. A stratified analysis of these 78 patients was not presented in the abstract. In this cohort of patients with CIED infection, Micra was implanted successfully in 98 patients and the previous CIED was explanted the same day as Micra was implanted in 36% of patients. Major complications were reported in 2% of patients with an average follow-up of 5.5 months. Six deaths were reported but none was related to the Micra Transcatheter Pacing System or the procedure.
 
Section Summary: Individuals with Guidelines-Based Indication for a Ventricular Pacing System who are Medically Ineligible for a Conventional Pacing System
No studies that exclusively enrolled patients who were medically ineligible to receive a conventional pacing system were identified. However, a subgroup of patients in whom use of conventional pacemakers was precluded was enrolled in the pivotal as well as the postapproval trial. Information on the outcomes in these subgroups of patients from the postapproval study showed that Micra was successfully implanted in 98% of cases and safety outcomes were similar to the original cohort. Even though, the evidence is limited and long-term effectiveness and safety is unknown, the short-term benefits outweigh the risks as the complex tradeoff of adverse events for these devices need to be assessed in the context of lifesaving potential of pacing systems in patients who are ineligible for conventional pacing systems on the market.
 
SUMMARY OF EVIDENCE
For individuals with guidelines-based indication for a ventricular pacing system who are medically eligible to receive a conventional pacing system who are treated with Micra transcatheter pacing system, the evidence includes a pivotal prospective cohort study a 1 postapproval prospective cohort study. Relevant outcomes are other test performance, treatment-related mortality, and treatment-related morbidity. Results at 6 months and 1 year for the pivotal study reported high procedural success (above 99%) and device effectiveness (pacing capture threshold met in 98% patients). Majority of the system or procedural-related complications occur within 30 days. At 1 year, the incidence of major complication did not increase substantially from 6 months (3.5% at 6 months vs 4% at 1 year). Results of the postapproval study were consistent with pivotal study and showed a lower incidence of major complications at -30 days as well as 1 year (1.5% and 2.7%, respectively). In both studies, the point estimates of major complication were lower than the pooled estimates from 6 studies of conventional pacemakers used as a historical comparator. While Micra Transcatheter Pacing System eliminates lead- and surgical pocket-related complications, its use can result in potentially more serious complication related to implantation/release of the device (traumatic cardiac injury) and less serious complications related to the femoral access site (groin hematomas and access site bleeding). Considerable uncertainties and unknowns remain in terms of durability of device and end of life device issues. Early and limited experience suggests that retrieval of these devices is unlikely because, in due course, the devices will be encapsulated. There is limited data on device-device interactions (both electrical and mechanical), which may occur when there is a deactivated Micra device alongside another leadless pacemaker or when a leadless pacemaker and transvenous device are both present. While the current evidence is encouraging, overall benefit with broad use of Micra transcatheter pacing system compared to conventional pacemakers has not been shown. The evidence is insufficient to determine the effects of technology on health outcomes.
 
For individuals with guidelines-based indication for a ventricular pacing system who are medically ineligible for a conventional pacing system who are treated with Micra transcatheter pacing system, the evidence includes subgroup analysis of a pivotal prospective cohort study and a postapproval prospective cohort study. Relevant outcomes are other test performance, treatment-related mortality, and treatment-related morbidity. Information on the outcomes in the subgroup of patients from the postapproval study showed that Micra was successfully implanted in 98% of cases and safety outcomes were similar to the original cohort. Even though, the evidence is limited and long-term effectiveness and safety is unknown, the short-term benefits outweigh the risks as the complex tradeoff of adverse events for these devices need to be assessed in the context of lifesaving potential of pacing systems in patients who are ineligible for conventional pacing systems. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
SUPPLEMENTAL INFORMATION
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American College of Cardiology Foundation et al
The American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society’s focused update (2012) on device-based therapy of cardiac rhythm abnormalities incorporated into their joint 2008 guidelines for device-based therapy of cardiac rhythm abnormalities does not include recommendations on leadless cardiac pacemakers (Epstein, 2013).
 
The 2012 Heart Rhythm Society and American College of Cardiology Foundation expert consensus statement on pacemaker device and mode selection did not include recommendations on leadless cardiac pacemakers (Gillis, 2012).
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
 
Some currently unpublished trials that might influence this review are listed below:
 
  • NCT 03039712 Longitudinal Coverage with Evidence Development Study on Micra Leadless Pacemakers (Micra DED).   Planned Enrollment: 37000  Completion Date: Jun 2021
  • NCT02610673 WiCS-LV Post Market Surveillance Registry
  Planned Enrollment 100  Completion Date: Nov 2021
  • NCT02536118 Micra Transcatheter Pacing System Post-Approval Registry
  Planned Enrollment 3100  Completion Date: Aug 2026
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement. The key literature is summarized below.
 
Aveir Leadless Pacemaker
The pivotal investigational device exemption (IDE) trial of the Aveir leadless pacemaker (LEADLESS II - Phase 2; NCT04559945) was a multicenter, prospective single cohort study enrolling 200 patients with a guidelines-based indication for single-chamber pacing (FDA, 2022). Primary results from the IDE trial have been summarized in a published research correspondence and FDA documents (Reddy, 2022; FDA, 2022).
 
Implantation of the Aveir leadless pacing system was successful in 196/200 (98%) trial subjects (mean age, 75.6 years; 37.5% female). The primary indication for pacing was chronic atrial fibrillation with 2nd or 3rd degree atrioventricular block (52.5%). The trial had 2 primary endpoints related to safety and efficacy. The trial would meet its safety endpoint if the lower bound of the 97.5% CI for the complication-free rate exceeded 86% at 6 weeks. A complication was defined as a device-or-procedure-related serious adverse event, including those that prevented initial implantation. The trial would meet its efficacy endpoint if the lower bound of the 97.5% CI for the composite success rate exceeded 85% at 6 weeks. The confirmatory effectiveness endpoint was considered met if the pacing threshold voltage is less than or equao to 2.0 V at 0.4 ms and the sensed R-wave amplitude is either greater than or equal to 5.0 mV at the 6-week visit or greater than or equal to the value at implant.
 
At 6 weeks, the trial met both of its confirmatory safety and efficacy endpoints, including freedom from device-or-procedure-related complications in 96% of patients (95% CI, 92.2 to 98.2), compared with a performance goal of 86%, and a composite success rate of 95.9% of patients (95% CI, 92.1 to 98.2), compared with a performance goal of 85%. The 6-month complication-free rate was 94.9% (95% CI, 90.0 to 97.4). The most frequent complications included 3 cardiac tamponade events and 3 premature deployment events. The rate of cardiac perforation/tamponade/pericardial effusion was 1.5%. No dislodgement events were reported in the Aveir cohort.
 
Confirmatory secondary endpoints included assessment of an appropriate and proportional rate-response during a Chronotropic Assessment Exercise Protocol (CAEP) exercise protocol and an estimated 2-year survival rate. The CAEP assessment was initiated in 23 subjects, of which 17 were considered analyzable. The rate-response slope was 0.93 (95% CI, 0.78 to 1.08), which fell within the prespecified range of 65% to 135%. The estimated 2-year survival rate based on the Nanostim Phase 1 cohort (N=917) was 85.3% (95% CI, 82.7 to 87.4), which exceeded the performance goal of 80%.
 
The current evidence on the use of the Aveir device is limited by a lack of adequate data on quality of life, long-term safety, effectiveness, reliability, and incidence of late device failures and battery longevity. While the device is designed to be retrieved when therapy needs evolve or the device needs to be replaced, there is currently inadequate clinical experience with issues related to devices that have reached end-of-life. Survival data for the currently marketed version of the Aveir device has not been reported.
Continued FDA approval of the Aveir transcatheter pacing system is contingent on the results of the Aveir VR Real-World Evidence Study (FDA, 2022). This post-approval study is designed to evaluate the long-term safety of the Aveir device in a real-world sample of 2100 participants. Both acute and long-term safety will be evaluated as post implant complication-free rates at 30-days and 10-years. Six-month and 10-year reports are due in September 2022 and March 2032, respectively.

CPT/HCPCS:
0387TTranscatheter insertion or replacement of permanent leadless pacemaker, ventricular
0388TTranscatheter removal of permanent leadless pacemaker, ventricular
0389TProgramming device evaluation (in person) with iterative adjustment of the implantable device to test the function of the device and select optimal permanent programmed values with analysis, review and report, leadless pacemaker system
0390TPeri procedural device evaluation (in person) and programming of device system parameters before or after a surgery, procedure or test with analysis, review and report, leadless pacemaker system
0391TInterrogation device evaluation (in person) with analysis, review and report, includes connection, recording and disconnection per patient encounter, leadless pacemaker system
0515TInsertion of wireless cardiac stimulator for left ventricular pacing, including device interrogation and programming, and imaging supervision and interpretation, when performed; complete system (includes electrode and generator [transmitter and battery])
0516TInsertion of wireless cardiac stimulator for left ventricular pacing, including device interrogation and programming, and imaging supervision and interpretation, when performed; electrode only
0517TInsertion of wireless cardiac stimulator for left ventricular pacing, including device interrogation and programming, and imaging supervision and interpretation, when performed; pulse generator component(s) (battery and/or transmitter) only
0518TRemoval of only pulse generator component(s) (battery and/or transmitter) of wireless cardiac stimulator for left ventricular pacing
0519TRemoval and replacement of wireless cardiac stimulator for left ventricular pacing; pulse generator component(s) (battery and/or transmitter)
0520TRemoval and replacement of wireless cardiac stimulator for left ventricular pacing; pulse generator component(s) (battery and/or transmitter), including placement of a new electrode
0521TInterrogation device evaluation (in person) with analysis, review and report, includes connection, recording, and disconnection per patient encounter, wireless cardiac stimulator for left ventricular pacing
0522TProgramming device evaluation (in person) with iterative adjustment of the implantable device to test the function of the device and select optimal permanent programmed values with analysis, including review and report, wireless cardiac stimulator for left ventricular pacing
33274Transcatheter insertion or replacement of permanent leadless pacemaker, right ventricular, including imaging guidance (eg, fluoroscopy, venous ultrasound, ventriculography, femoral venography) and device evaluation (eg, interrogation or programming), when performed
33275Transcatheter removal of permanent leadless pacemaker, right ventricular, including imaging guidance (eg, fluoroscopy, venous ultrasound, ventriculography, femoral venography), when performed

References: American Heart Association(2016) Statement of the American Heart Association to the Food and Drug Administration Circulatory System Devices Panel February 18, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM486235.pdf. Accessed August 6, 2018.

Centers for Medicare & Medicaid Services.(2017) Decision Memo for Leadless Pacemakers (CAG-00448N). 2017; https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=285&bc=ACAAAAAAQAAA&. Accessed August 31, 2018.

Cohen M, Bush D, VetterV, et al.(2001) Permanent epicardial pacing in pediatric patients: seventeen years of experience and 1200 outpatient visits. Circulation. 2001 May 29;103(21):2585-90.

Duray GZ, Ritter P, El-Chami M, et al.(2017) Long-term performance of a transcatheter pacing system: 12-Month results from the Micra Transcatheter Pacing Study. Heart Rhythm. May 2017;14(5):702-709. PMID 28192207

Epstein AE, DiMarco JP, Ellenbogen KA, et al.(2012) 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. Jan 22 2013;61(3):e6-75. PMID 23265327

FDA Presentation(2018) Circulatory System Devices Panel Meeting: Leadless Pacemakers. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM486733.pdf. Accessed August 6, 2018.

Fernández AL, García-Bengochea JB, Ledo R, et al.(2004) Minimally invasive surgical implantation of left ventricular epicardial leads for ventricular resynchronization using video-assisted thoracoscopy. Rev Esp Cardiol. 2004 Apr;57(4):313-9.

Food and Drug Administration.(2016) FDA Executive Summary Memorandum General General Issues: Leadless Pacemaker Devices Prepared for the February 18, 2016 meeting of the Circulatory System Devices Advisory Panel Gaithersburg Hilton; Gaithersburg, MD. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM485093.pdf. Accessed August 6, 2018.

Food and Drug Administration.(2018) Summary of Safety and Effectiveness Data (SSED): Micra® Transcatheter Pacing System. https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150033B.pdf. Accessed August 6, 2018.

Gillis AM, Russo AM, Ellenbogen KA, et al.(2012) HRS/ACCF expert consensus statement on pacemaker device and mode selection. J Am Coll Cardiol. Aug 14 2012;60(7):682-703. PMID 22854177

Healey JS, Toff WD, Lamas GA, et al.(2006) Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation. Jul 4 2006;114(1):11-17. PMID 16801463

Kempa M, Laskawski G, Budrejko S, et al.(2019) Implantation of a dual-chamber pacemaker with epicardial leads in adults using a minimally invasive subxyphoid approach. Pacing Clin Electrophysiol. 2019 May;42(5):537-541. doi: 10.1111/pace.13651. Epub 2019 Mar 18.

Kirkfeldt RE, Johansen JB, Nohr EA, et al.(2011) Risk factors for lead complications in cardiac pacing: a population-based cohort study of 28,860 Danish patients. Heart Rhythm. Oct 2011;8(10):1622-1628. PMID 21699827

Kirkfeldt RE, Johansen JB, Nohr EA, et al.(2014) Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark. Eur Heart J. May 2014;35(18):1186-1194. PMID 24347317

Knops RE, Tjong FV, Neuzil P, et al.(2015) Chronic performance of a leadless cardiac pacemaker: 1-year follow-up of the LEADLESS trial. J Am Coll Cardiol. Apr 21 2015;65(15):1497-1504. PMID 25881930

Kubus p, Materna o, Gebauer,R, et al.(2012) Permanent epicardial pacing in children: long-term results and factors modifying outcome. Europace. 2012 Apr;14(4):509-14. doi: 10.1093/europace/eur327. Epub 2011 Oct 11.

Lakkireddy D, Knops R, Atwater B, et al.(2017) A worldwide experience of the management of battery failures and chronic device retrieval of the Nanostim leadless pacemaker. Heart Rhythm. Dec 2017;14(12):1756-1763. PMID 28705736

Lau KC, William-Gaynor j, Fuller SM, et al.(2015) Long-term atrial and ventricular epicardial pacemaker lead survival after cardiac operations in pediatric patients with congenital heart disease. Heart Rhythm. 2015 Mar;12(3):566-573. doi: 10.1016/j.hrthm.2014.12.001. Epub 2014 Dec 4.

Lloyd M, Reynolds D, Sheldon T, et al.(2017) Rate adaptive pacing in an intracardiac pacemaker. Heart Rhythm. Feb 2017;14(2):200-205. PMID 27871854

Micra Physician Brochure. http://www.medtronic.com/content/dam/medtronic-com/01_crhf/brady/pdfs/medtronic-micra-transcatheter-pacing-system-hcp-brochure.pdf. Accessed August 6, 2018.

Mikhael F. El-Chami M, et.al.(2018) Leadless Pacemaker Implant in Patients with Pre-Existing Infections:Results from the Micra Post-Approval Registry. Paper presented at: Heart Rhythm Scientific Sessions (May 10, 2018)2018; Boston, Massachusetts.

Reddy VY, Exner DV, Cantillon DJ, et al.(2015) Percutaneous Implantation of an Entirely Intracardiac Leadless Pacemaker. N Engl J Med. Sep 17 2015;373(12):1125-1135. PMID 26321198

Reddy VY, Exner DV, Doshi R, et al.(2022) Primary Results on Safety and Efficacy From the LEADLESS II-Phase 2 Worldwide Clinical Trial. JACC Clin Electrophysiol. Jan 2022; 8(1): 115-117. PMID 34863657

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Reddy VY, Miller MA, Knops RE, et al.(2016) Retrieval of the Leadless Cardiac Pacemaker: A Multicenter Experience. Circ Arrhythm Electrophysiol. Dec 2016;9(12). PMID 27932427

Reynolds D, Duray GZ, Omar R, et al.(2016) A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med. Feb 11 2016;374(6):533-541. PMID 26551877

Ritter P, Duray GZ, Steinwender C, et al.(2015) Early performance of a miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study. Eur Heart J. Oct 1 2015;36(37):2510-2519. PMID 26045305

Ritter P, Duray GZ, Zhang S, et al.(2015) The rationale and design of the Micra Transcatheter Pacing Study: safety and efficacy of a novel miniaturized pacemaker. Europace. May 2015;17(5):807-813. PMID 25855677

Roberts PR, Clementy N, Al Samadi F, et al.(2017) A leadless pacemaker in the real-world setting: The Micra Transcatheter Pacing System Post-Approval Registry. Heart Rhythm. Sep 2017;14(9):1375-1379. PMID 28502871

Sperzel J, Defaye P, Delnoy PP, et al.(2018) Primary safety results from the LEADLESS Observational Study. Europace. Sep 01 2018; 20(9): 1491-1497. PMID 29365073

Tjong FVY, Knops RE, Neuzil P, et al.(2018) Midterm Safety and Performance of a Leadless Cardiac Pacemaker: 3-Year Follow-up to the LEADLESS Trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System). Circulation. Feb 6 2018;137(6):633-635. PMID 29431664

U.S. Food and Drug Administration (FDA).(2021) Letter to Health Care Providers. Leadless Pacing Systems: Risk of Major Complications Related to Cardiac Perforation During Implantation. November 17, 2021; https://www.fda.gov/medical-devices/letters-health-care-providers/leadless-pacing-systems-risk-major-complications-related-cardiac-perforation-during-implantation. Accessed April 7, 2022.

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